The invention is described in the following using the example of a method for preparing tissue for use for an artificial heart valve. Although the present invention is particularly suitable for preparing this type of tissue, it is not limited to this application. The present invention can also be used to prepare blood vessels, skin tissue, ligaments, or the like.
There are basically two different types of heart valve prostheses: mechanical valves, which are artificially produced, usually being made of graphite coated with pyrolytic carbon; and biological prostheses, which are often made of pericardial tissue, which is usually obtained from animal sources (e.g. swine or cattle). The heart valve formed of biological tissue is usually mounted in a base body (e.g. a rigid plastic framework or a self-expanding stent), which is then implanted at the position of the natural valve. The present invention describes a method for preparing such tissue for use in a heart valve prosthesis, which performs the function of a natural heart valve.
The tissue of origin must be thoroughly cleaned and prepared before implantation. In so doing, the tissue is modified, to the greatest extent possible, such that the tissue is not recognized by the body as foreign tissue, is not calcified, and has the longest life span possible. Such a method for the preparation of tissue substantially comprises a plurality of steps.
One possible preparation step is the so-called decellularization of the tissue. In this step, cell membranes, intracellular proteins, cell nuclei, and other cellular components are removed as completely as possible from the tissue in order to obtain the purest extracellular matrix possible. Any cells and cellular components remaining in the tissue could potentially cause an unwanted calcification of the biological implant material. The decellularization should be performed in a manner that is so gentle that the structure of the extracellular matrix and the collagen fibers in the extracellular matrix remain as unaffected as possible while ensuring that all cells and cell components contained therein are removed from the tissue.
Another possible preparation step is that of cross-linking the extracellular matrix, in particular the collagen fibers, of the tissue. After decellularization, preferably all cellular components have been removed from the tissue and the biological material consists of only the extracellular matrix. In the case of pericardial tissue, the extracellular matrix is formed primarily of collagen fibers. In order to obtain biological material having the most optimal mechanical properties possible and to prevent rejection reactions by the receiving body, the collagen fibers are cross-linked by means of a suitable cross-linking agent via the incorporation of chemical bonds. The cross-linking agent binds to free amino groups of the collagen fibers and forms chemically stable compounds between collagen fibers. A biological material having long-term stability is thereby obtained from the three-dimensionally arranged collagen fibers, wherein this biological material is no longer recognized as foreign biological material. The stability and strainability of the tissue is markedly increased by means of the three-dimensional cross-linking or linking of the individual collagen fibers via the cross-linking agent. This is decisive, in particular, in the case of use as tissue of a heart valve, where the tissue is intended to open and close, in brief intervals, as a valve.
The thusly treated tissue is secured to a support body, usually via suturing. The support body or the support frame can be implanted using surgical techniques. As an alternative, the support frame is self-expanding or can be expanded by means of a balloon such that the heart valve prosthesis can be guided, in the compressed state, to the site of implantation by means of a catheter and can be implanted inside the natural valve.
According to the prior art, such heart valve prostheses, which can be implanted by means of a catheter, are stored in a storage solution, i.e., in the moist state. The storage solution is used for the sterile stabilization of the biological tissue. For implantation, the heart valve prosthesis must then be removed from the storage solution in the surgical suite and, after a plurality of rinsing processes, must be mounted on the catheter. This assembly of the heart valve prosthesis in the surgical suite itself is complex and requires a great deal of work. In addition, whether or not the assembly is carried out correctly depends on the skills of the particular surgical team.
Approaches are therefore known in the prior art for drying such biological tissue, and for processing and sterilizing said biological tissue in the dried state. This would make it possible to sterilize, sterile-package, and pre-assemble a total system comprising a catheter and a pre-assembled heart valve prosthesis.
A method for the preparation of a heart valve prosthesis, which includes the processing of dried, biological material, is disclosed in U.S. Pat. No. 8,105,375. According to the method disclosed therein, the biological tissue is fixed or cross-linked with an aldehyde-containing solution (e.g., glutaraldehyde or formaldehyde solution) and, before drying, is treated with at least one aqueous solution, which contains at least one biocompatible and non-volatile stabilizer. The stabilizers that are disclosed are hydrophilic hydrocarbons comprising a plurality of hydroxyl groups and, as examples, water-soluble sugar alcohols such as glycerol, ethylene glycol or polyethylene glycol are mentioned.